Simulation shows how transporter proteins do their work in cells

Stanford researchers have simulated how a transporter protein moves a sugar molecule through a cell membrane, a phenomenon with relevance to drug delivery. Credit: iStock/NNehring, with Stefani Billings

Inside every plant or animal, proteins called transporters act as cellular doorkeepers, letting nutrients and other molecules in or out as need be. Although transporter proteins are critical for normal cell function – and are key targets for many drugs – scientists have never really understood how they open and close.

Now Stanford researchers have created a realistic simulation of a transporter protein moving a sugar molecule across a cell membrane. The simulation, described in Cell, could improve the development of drugs, many of which work by manipulating transporters. For example, these proteins ferry dopamine, serotonin and other neurotransmitters in and out of cells, making them key points of interest for treating psychiatric disorders such as depression. In addition, most drugs must evade ejection from cells by transporters to be effective.

"Now that we have a better understanding of how transporters work we can break down the process and see what's actually important," says Liang Feng, an assistant professor in molecular and cellular physiology, who co-authored the paper with Ron Dror, an associate professor of computer science.

Transporter basics

Transporter proteins sit snugly in the cell membrane. They have two gates: One opens to the outside of the cell and the other to the inside. In the late 1960s, scientists theorized that transporters could only have one gate open at a time, much like an airlock system in a spacecraft. But since proteins are too small to be seen through a microscope it wasn't possible to verify the idea.

Instead, scientists had used a technique called crystallography to decipher the shape of a protein. Combining such static images with biological experiments, they could extrapolate how transporter proteins might behave.

But Feng wanted to go further. "We wanted to figure out how these molecules change shape to realize their function," he said.

Dynamic simulation

Simulations show how sugar is transported across the cell membrane. Transporter proteins, represented by yellow and purple ribbons, change their structure to do their work. The first simulation begins with the protein in the outward-open structure, which allows a pink sugar molecule to move up and out. In the second simulation, the protein begins in the same outward-open structure but then transforms to the inward-open structure, allowing the sugar molecule to move down and into the cell. Credit: Stanford University

The more dynamic view of a transporter in action came about through conversations between graduate students Nathan Fastman and Naomi Latorraca. Fastman, a graduate student in Feng's lab, was intimately familiar with a particular sugar transporter. Latorraca was a graduate student in Dror's lab who specialized in modeling molecular dynamics on an atomic level. These types of simulations have become more powerful with improvements in computer technology.

"Plus, the underlying physics models have become more accurate, and we now use better algorithms," Dror said.

Fastman discovered crystallography images of a transporter in different stages of the transport process, which provide starting points for simulations. Starting with just one structure, Latorraca and Dror programmed in the physical forces between atoms, then stepped back and let the simulated atoms move spontaneously.

From that starting point, the simulation found structures that match the two other crystallographic states. The simulation also supported the airlock theory of how the transporter worked. It showed that the forces between the atoms are such that the protein is most stable with just one or the other of the two doors open, or with both closed, but not with both open.

"The beauty of this paper is the simulation and the experimental evidence match really well, so we know the simulation is very likely to be real," Feng said.

Dror said revealing the inner workings of transporters will benefit medical research.

"For example, one could treat diseases like diabetes by creating drugs that bind to and regulate transporters," he said, "and preventing drugs from getting thrown out of cells by transporters would help avoid problems such as antibiotic resistance."

Related Stories

Researchers at Vanderbilt University Medical Center have mapped the conformational changes that occur in a protein "notorious" for pumping chemotherapeutic drugs out of cancer cells and blocking medications from reaching ...

How is drug resistance of cancer cells affected by ABC-transporters? A new research paper, published in the open access journal BioDiscovery, looks at the complex relationship between the second generation of tyrosine kinase ...

When nerve cells have to communicate with each other in our brains, it involves release of small signal molecules, the so-called neurotransmitters, which act as chemical messengers in specific points of contact between nerve ...

Most physiological processes are pH-sensitive, and pH within individual cells in skeletal muscles (pHi) must be carefully regulated to maintain normal cellular functioning. During intensive exercise, and also in certain diseases, ...

Professor of Biochemistry Emad Tajkhorshid and colleagues have discovered that membrane transporters help not just sugars and other specific substrates cross from one side of a cellular membrane to the other—water also ...

Human cells are protected by a largely impenetrable molecular membrane, but researchers have built the first artificial transporter protein that carries individual atoms across membranes, opening the possibility of engineering ...

Researchers at Duke University have created a framework for helping bioengineers determine when to use multiple lines of cells to manufacture a product. The work could help a variety of industries that use bacteria to produce ...

A team of researchers with the University of Tübingen in Germany has found an example of a fish that is able to control light reflected from organs next to its pupils—a form of photolocation. In their paper published in ...

1 comment

Except that many "transporter" proteins are actually pheromone receptor proteins. We should hypothesize functions for found molecules rather than branding them prematurely with names that will only deter competent investigation following on. The fact is that incompetents, like Ranvier, label like crazy and drive subsequent investigators crazy, too.

Please sign in to add a comment.
Registration is free, and takes less than a minute.
Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.